A number of studies have indicated that prolonged, major depression disorder (MDD) is associated with a selective loss of hippocampal volume that persists long after the depression has resolved. Ionotropic glutamate receptor subtypes and apoptotic cell death pathways are very likely to be involved in this process. The induction of endogenous neuronal pathways, such as those increasing brain-derived neurotrophic factor (BDNF) levels, can prevent neuronal loss. The interplay of ionotropic glutamate receptor (IGR) activation, particularly receptors of the NMDA subtype, neurotrophin release and synthesis are critical to maintaining neuronal viability. Genetic variation in IGR genes, neurotrophin genes, and stress pathways are likely to profoundly influence neuronal viability. BDNF interacts with a receptor tyrosine kinase (TrkB), allowing for neuronal survival and synaptic strengthening. There is growing interest in the BDNF and the TrkB genes as candidates for vulnerability to addictions and other psychiatric conditions, including anxiety and MDD. MDD shares significant comorbidity with alcoholism and other disorders such as schizophrenia, although the relationship between the diagnoses is not well understood. From the foregoing discussion it could be expected that BDNF variation might influence behavior. Several recent studies have looked at the relationship between the functional BDNF Val66Met variant and psychopathology in humans. The results have been conflicting. Apart from differences in study design, genotyping, and data analysis, one possibility for this lack of consensus is that other BDNF functional alleles may be present and have a role in psychopathology. In one study, we tested the hypothesis that a functional and abundant missense polymorphism in the coding region of the BDNF gene (Val66Met) was associated with the volume of the hippocampal formation in patients with schizophrenia and healthy comparison subjects. One hundred twenty four contiguous T1-weighted coronal MR images (slice thickness = 1.5mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5T GE imaging system in 21 patients with schizophrenia and 25 healthy comparison subjects. Volumes of the right and left hippocampal formation were measured manually by an operator blind to group status and genotype. All participants were genotyped for the BDNF Val66Met polymorphism. Analyses revealed a main effect of BDNF Val66Met genotype, but no significant group-by-genotype interaction. Val/Val homozygotes (N = 28) had larger hippocampal volumes compared to Val/Met heterozygotes (N = 18). BDNF Val66Met genotype accounted for approximately 21% of the variance in the volume of the hippocampal formation. These findings implicate genetic involvement of BDNF in variation of human hippocampal volume. In another study, we used variant discovery approaches to identify new variants in BDNF promoter regions. In addition, genotyping was performed in U.S. Caucasian, American Indian, and African American populations. Lifetime DSM-III-R psychiatric diagnoses were assigned and the Tridimensional Personality Questionnaire (TPQ) administered to measure anxious temperament (harm avoidance [HA]) and novelty seeking (NS). A novel SNP was discovered (nt -281) in BDNF promoter 1 with decreased DNA binding in vitro and decreased basal reporter gene activity in transfected rat hippocampal neurons. The frequency of the -281A allele was 0.03 in a Caucasian sample but was virtually absent in other populations. Single allele-based association studies in a community-based Caucasian sample showed that individuals with the -281A allele (13 heterozygotes) had lower TPQ HA (F = 4.8, p < 0.05) and were less likely to have a psychiatric diagnosis (0.69 v 0.47, ?2 = 2.4, p = 0.12). In contrast, the Met 66 allele was associated with increased HA (F = 4.1, p = 0.02) and was most abundant in individuals with both anxiety disorders and major depression (p < 0.05). In this population, the low activity ?281A allele may be protective against anxiety and psychiatric morbidity whereas Met 66 may be a risk allele.